Osteoporosis is a pathologic state or disease entity characterized by a loss of bone mass over a certain level thereby giving rise to certain symptoms or increasing one's risk for getting the symptoms. Its major symptoms are spinal kyphosis and compression fracture of the dorsolumbar vertebrae and vertebral bodies, neck of the femur, distal end of the radius, the rib, proximal end of the humerus, and other bones. In bone tissues, normally bone formation and resorption are going on at matched rates, with osteoblasts and osteoclasts playing central roles in the formation and resorption, respectively. However, when the balance of bone formation and bone resorption is disrupted in favor of resorption, a net loss of bone mass results. Therefore, drugs capable of inhibiting bone resorption are considered useful for the prophylaxis and therapy of osteoporosis and several bone resorption inhibitors such as estrogens and calcitonins have been suggested in the treatment of osteoporosis. However, these drugs have various deficiencies, some are restricted in the scope of indication and/or indefinite in efficacy so that no satisfactory responses have been clinically obtained others can be associated with various other health risks. Therefore, a demand exists for a new prophylactic/therapeutic regimen for increased bone resorption.
Recently it has become clear that cathepsin L, a protease secreted from osteoclasts in the process of resorption, is a major factor in the degradation of the bone matrix protein, collagen. Therefore, it is believed that the decomposition of bone collagen due to resorption can be controlled by inhibiting cathepsin L activity and that this approach is useful for the prophylaxis and therapy of osteoporosis. Heretofore, a few substances including leupeptin and antipain as well as the epoxysuccinic acid derivatives disclosed in Japanese published unexamined patent application (Kokai tokkyo koho hei) Nos.2-304074, 2-304075 and 2-304085 are reported to have cathepsin L inhibitory activity as one of their inhibition activities.
Lactol derivatives having an 3-amino-2-hydroxyfuran or 3-amino-2-hydroxypyran skeleton namely, the compounds described in Tetrahedron Letters, 30, 5421 (1989), Canadian Journal of Chemistry, 60, 558 (1982), Canadian Journal of Chemistry, 56, 119 (1978), European Journal of Medicinal Chemistry, 12, 317 (1977), and Chemical and Pharmaceutical Bulletin, 16, 1881 (1968) [all of which are incorporated herein by reference], for instance, are known. However, none of the literature allude to these compounds having any cathepsin L inhibitory activity. Nor is any compound formed by coupling the 3-amino group of the 3-amino-2-hydroxyfuran or 3-amino-2-hydroxypyran skeleton to an amino acid derivative known.
However, epoxysuccinic acid derivatives inhibit not only cathepsin L but also other proteases as acknowledged in the above patent literature, but those compounds have not been implemented as a prophylactic/therapeutic drug for osteoporosis.